Abstract
During metastatic progression, circulating cancer cells become lodged within the microvasculature of end organs, where most die from mechanical deformation. Although this phenomenon was first described over a half-century ago, the mechanisms enabling certain cells to survive this metastasis-suppressive barrier remain unknown. By applying whole-transcriptome RNA-sequencing technology to isogenic cancer cells of differing metastatic capacities, we identified a mutation encoding a truncated form of the pannexin-1 (PANX1) channel, PANX1(1-89), as recurrently enriched in highly metastatic breast cancer cells. PANX1(1-89) functions to permit metastatic cell survival during traumatic deformation in the microvasculature by augmenting ATP release from mechanosensitive PANX1 channels activated by membrane stretch. PANX1-mediated ATP release acts as an autocrine suppressor of deformation-induced apoptosis through P2Y-purinergic receptors. Finally, small-molecule therapeutic inhibition of PANX1 channels is found to reduce the efficiency of breast cancer metastasis. These data suggest a molecular basis for metastatic cell survival on microvasculature-induced biomechanical trauma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Breast Neoplasms / blood supply
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cells, Cultured
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Connexins / antagonists & inhibitors
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Connexins / genetics*
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Connexins / metabolism
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Gene Expression Regulation, Neoplastic
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HEK293 Cells
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Humans
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Immunoblotting
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Interleukin Receptor Common gamma Subunit / genetics
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Interleukin Receptor Common gamma Subunit / metabolism
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Microscopy, Confocal
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Mutation
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Neoplasm Metastasis
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Neovascularization, Pathologic / genetics*
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / prevention & control
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Oligonucleotide Array Sequence Analysis
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RNA Interference
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Small Molecule Libraries / pharmacology
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Stress, Mechanical
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Transcriptome
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Transplantation, Heterologous
Substances
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Connexins
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Il2rg protein, mouse
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Interleukin Receptor Common gamma Subunit
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Nerve Tissue Proteins
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PANX1 protein, human
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Small Molecule Libraries
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Adenosine Triphosphate